Inhibition of constitutive signaling of Kaposi's sarcoma-associated herpesvirus G protein-coupled receptor by protein kinases in mammalian cells in culture.
Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8, which is consistently present in tissues of patients with Kaposi's sarcoma and primary effusion lymphomas, contains a gene that encodes a G protein-coupled receptor (KSHV-GPCR). We recently showed that KSHV-GPCR exhibits constitutive signaling via activation of phosphoinositide-specific phospholipase C and stimulates cell proliferation and transformation. In this study, we determined whether normal cellular mechanisms could inhibit constitutive signaling by KSHV-GPCR and thereby KSHV-GPCR-stimulated proliferation. We show that coexpression of GPCR-specific kinases (GRKs) and activation of protein kinase C inhibit constitutive signaling by KSHV-GPCR in COS-1 monkey kidney cells and in mouse NIH 3T3 cells. Moreover, GRK-5 but not GRK-2 inhibits KSHV-GPCR-stimulated proliferation of rodent fibroblasts. These data provide evidence that cell regulatory pathways of receptor desensitization may be therapeutic targets in human diseases involving constitutively active receptors.
Geras-Raaka
E
E
Division of Molecular Medicine, the Department of Medicine, the Department of Medicine, Cornell University Medical College, New York 10021, USA.
Arvanitakis
L
L
Bais
C
C
Cesarman
E
E
Mesri
E A
EA
Gershengorn
M C
MC
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002455:Cell Division; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D054774:G-Protein-Coupled Receptor Kinase 5; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000472:pathogenicity*; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D011493:Protein Kinase C / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*; D019707:Receptors, Chemokine / Q000502:physiology*; D012514:Sarcoma, Kaposi / Q000821:virology*; D015398:Signal Transduction; D014162:Transfection; D014764:Viral Proteins / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases
D007295:Inositol Phosphates; C105181:ORF74 protein, Human herpesvirus 8; D019707:Receptors, Chemokine; D014764:Viral Proteins; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D051552:beta-Adrenergic Receptor Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; C517895:Grk5 protein, mouse